Over the years, it has become evident that pharmacotherapy of major central nervous system (CNS) diseases such as depression, bipolar disorder, schizophrenia and anxiety disorders rely on drugs that target multiple CNS receptors simultaneously (Kalali et al., (2012) Essential CNS Drug Development; Cambridge University Press: New York; Conn & Roth (2008) Neuropsychopharmacol. 33: 2048). For instance, the superior efficacy and improved side-effect profiles of atypical antipsychotics such as lurasidone, ziprasidone and aripiprazole, have been attributed to their broad spectrum of activities involving dopaminergic, serotonergic and even cholinergic neurotransmission (Davies et al., (2004) CNS Drug Rev. 10: 317). In the same way, antidepressants such as vilazodone, that target the reuptake of serotonin (5-HT) along with the 5-HT1A receptor are known to be fast acting, efficacious and tolerable (Cruz, M. P. (2012) Pharmacy Ther. 37: 28; Celada et al. (2013) CNS Drugs 27: 703). However, a more defined combination of pharmacological activities at these and other targets is desirable for such agents to offer optimum therapeutic benefits in treating diseases of CNS origin.
It is now well established that targeting the D2-like receptors (D2, D3 and D4, antagonists), 5-HT1A (agonists), 5-HT2A (antagonists) and 5-HT7 (antagonists) are desirable features in the pharmacotherapy for schizophrenia (Roth & Meltzer (1995) The Role of Serotonin in Schizophrenia in Psychopharmacology: The Fourth Generation of Progress; Bloom & Kupfer, Eds. Raven Press New York: New York; Gross & Geyer (2012) Current Antipsychotics, Handbook Exp. Pharmacol.; Springer-Verlag: Berlin Heidelberg, p 418). On the other hand, antidepressants may benefit from targeting the serotonin transporter (SERT), along with 5-HT1AR (agonist) and 5-HT7R (antagonist) for an improved profile (Abbas et al., (2009) Psychopharmacol. 205: 119; Artigas, F. Pharmacol. Ther. 2013, 137: 119; Stahl et al., (2013) Curr. Drug Targets 14: 578). With the introduction of the D2R partial agonist and functionally selective aripiprazole as a well-tolerated and effective antipsychotic, the drug development paradigm for schizophrenia has significantly shifted in a new and exciting direction (Lieberman, J. A. (2004) CNS Drugs 18: 251). The caveat for multiple receptor targeting has been that it may also lead to off-target activities that may culminate in unforeseen side effects. Therefore, as part of drug design strategy, there is also a focus on evaluating synthetic compounds at culprit receptors including the 5-HT2B receptors associated with valvular heart disease and the 5-HT2C and H1 weight-gain and sedation side-effects (Kroeze et al., (2003) Neuropsychopharmacol. 28: 519; Miller, D. D. (2004) Prim. Care Companion J. Clin. Psychiatry 6: 3; Opgen-Rhein et al., (2010) Pharmacogenomics 11: 773).
N-Alkylated tetrahydroisoquinolines have been at the center of discussion recently as key ligands for certain CNS receptors associated with major brain disorders (Vermeulen et al., (2004) J. Med. Chem. 47: 5451; Antkiewicz-Michaluk et al., (2014) J. Neurotox. Res. 26: 85; Noel et al., (2012) Bioorg. Med. Chem. Lett. 22: 3739). It has been previously reported that the tetrahydroisoquinoline (THIQ) moiety, appropriately substituted with arylalkyl groups such as benzothiazole alkyl groups or halobutyrophenones could produce agents that provide differential binding profiles at clinically relevant CNS receptors including serotonin (5-HT) and dopamine (DA) receptor subtypes (Zhu et al., (2012) Eur. J. Med. Chem. 53: 124; Ofori et al., (2016) Bioorg. Med. Chem. 24: 3464).